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Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited.This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment.Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P.001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival.MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility.

Summary Background Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma. Methods We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0–1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1–3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1–3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete. Findings Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28–45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7–4·1), 32 (74%; 95% CI 58·8–86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3–4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3–4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients. Interpretation Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young ( Funding Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

In January 2020, the first documented patient in the United States infected with severe acute respiratory syndrome coronavirus 2 was diagnosed in Washington State. Since that time, community spread of coronavirus disease 2019 (COVID-19) in the state has changed the practice of oncologic care at our comprehensive cancer center in Seattle. At the Seattle Cancer Care Alliance, the primary oncology clinic for the University of Washington/Fred Hutchinson Cancer Consortium, our specialists who manage adult patients with hematologic malignancies have rapidly adjusted clinical practices to mitigate the potential risks of COVID-19 to our patients. We suggest that our general management decisions and modifications in Seattle are broadly applicable to patients with hematologic malignancies. Despite a rapidly changing environment that necessitates opinion-based care, we provide recommendations that are based on best available data from clinical trials and collective knowledge of disease states.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

The BELIEF trial was an international study of belinostat in patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) that led to FDA-approval for the disease. Herein, we present a subset analysis of patients with angioimmunoblastic T-cell lymphoma (AITL). Patients with R/R PTCL received belinostat 1000mg/m(2) intravenously every 21 days. The primary study endpoint was ORR by Cheson 2007 criteria. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of 129 patients treated, 22 patients were diagnosed with AITL. The ORR for AITL patients was 45.5%, with 18% achieving compete response. After a median follow up of 21.5 months, the median DOR, PFS, and OS were 13.6 months, 4.2 months, and 9.2 months, respectively. Common grade 3/4 adverse events were asthenia, fatigue, cytopenias, and septic shock. Single-agent belinostat induces clinically meaningful duration of response in patients with AITL and warrants further investigation in studies.

PURPOSE To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS). PATIENTS AND METHODS CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria. RESULTS Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature. CONCLUSION Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.

Sezary syndrome (SS) is a form of cutaneous T-cell lymphoma (CTCL), demonstrating leukemic involvement of malignant T-cells. Known systemic sequelae of SS include hemophagocytic syndrome-induced anemia, normocytic anemia secondary to bone marrow infiltration, and pancytopenia. We report a patient with SS, initially demonstrating widespread morbilliform eruption, who presented with malignancy-related microangiopathic hemolytic anemia (MAHA). Our findings represent a novel presentation of SS that will inform the differential diagnosis and treatment of future SS patients presenting with anemia and thrombocytopenia.

Introduction The phase 3 ECHELON-2 study (NCT01777152) demonstrated that frontline treatment with brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL) (Horowitz S, et al. Lancet 2019). With a median follow-up of 36.2 months for progression-free survival (PFS), the hazard ratio (HR) (0.71 [95% confidence interval {CI}: 0.54, 0.93], P=0.01) favored A+CHP over CHOP. The median PFS was 48.2 months (95% CI: 35.2, not evaluable) versus 20.8 months (95% CI: 12.7, 47.6) for A+CHP and CHOP, respectively. With a median follow-up of 42.1 months for overall survival (OS), the HR (0.66 [95% CI: 0.46, 0.95], P=0.02) also favored A+CHP over CHOP. Median OS was not reached for either arm. With these results, A+CHP was the first treatment regimen to show an OS benefit over CHOP in this pt population. Herein, we report results with a median follow-up of 44.3 months for PFS and 55.5 months for OS. Methods ECHELON-2 is a phase 3, randomized, double-blind, double-dummy, placebo-controlled, active-comparator, multicenter study. Eligible adult pts with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) were randomized to A+CHP or CHOP for six or eight cycles. Randomization was stratified by histological subtype and international prognostic index score. The primary endpoint of PFS was assessed per blinded independent central review in the primary analysis and per investigator in this updated analysis. Key secondary endpoints were OS, PFS in sALCL, complete remission (CR) rate, and objective response rate (ORR). Subsequent therapies, including BV or BV-containing regimens, were permitted. Results A total of 452 pts were enrolled and randomized 1:1 with 226 pts in each arm. The study included pts with advanced disease (Stage III [27%] and Stage IV [53%]; IPI ≥2 [78%]); given target enrollment, most pts (316 [70%]) had sALCL (218 [48%] anaplastic lymphoma kinase [ALK]-negative and 98 pts [22%] ALK-positive). With additional follow-up, the HRs for PFS per investigator (0.70 [95% CI: 0.53, 0.91], P=0.0075) (Figure 1) and OS (0.74 [95% CI: 0.54, 1.02], P=0.0688) continue to favor A+CHP over CHOP. The median PFS was 63.5 months (95% CI: 42.0, not evaluable) versus 23.8 months (95% CI: 13.6, 55.9) for A+CHP and CHOP, respectively. The estimated 5-year PFS was 50.9% (95% CI: 42.1, 59.1) for the A+CHP arm versus 42.7% (95% CI: 35.3, 49.8) for the CHOP arm. Median OS was not reached for either arm. The estimated 5-year OS was 68.7% (95% CI: 61.3, 75.0) for the A+CHP arm versus 60.3% (95% CI: 52.8, 67.0) for the CHOP arm. The PFS analyses for key prespecified subgroups were generally consistent with the overall study results (Figure 2). In the subset of pts with sALCL, the HR for PFS (0.55 [95% CI: 0.39, 0.78]) also favors A+CHP over CHOP, with an estimated 5-year PFS of 59.8% (95% CI: 48.0, 69.7) for the A+CHP arm versus 48.1% (95% CI: 39.1, 56.6) for the CHOP arm. A total of 23 pts (10%) in the A+CHP arm (16 pts with sALCL, 4 pts with PTCL not otherwise specified, and 3 pts with angioimmunoblastic T-cell lymphoma) and 51 pts (23%) in the CHOP arm received subsequent systemic therapy with BV. In the A+CHP arm, the median time to retreatment was 12.3 months (range, 3, 51); 15 pts (ORR: 65%) had CR (9 pts) or partial remission (6 pts) after retreatment with BV monotherapy (21 pts) or BV-containing regimen (2 pts). With additional follow-up in pts with treatment-emergent peripheral neuropathy (PN) (117 pts A+CHP and 124 pts CHOP), 68% of pts in the A+CHP arm had either resolution or improvement of these events compared with 77% of pts in the CHOP arm. Of the pts with ongoing PN events at last follow-up, 73% in A+CHP arm and 74% in the CHOP arm had grade 1 events, 25% and 23% of pts, respectively, had grade 2 events, and 2% of pts in each arm had grade 3 events. Conclusions At 5 years, frontline treatment with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, including ongoing remission in ~60% of pts with sALCL, with a manageable safety profile, including continued resolution or improvement of PN. Additional 5-year results, including data from prespecified subgroups, will be presented. Disclosures Horwitz: C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Affirmed: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; ASTEX: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding. Pro:Verastem Oncology: Research Funding. Illidge:Takeda: Current Employment, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Iyer:Legend Biotech: Consultancy; Rhizen: Research Funding; Spectrum: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Bartlett:BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy; Forty Seven: Research Funding; Autolus: Research Funding; Acerta: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed Therapeutics: Research Funding; BMS/Celgene: Research Funding; Roche/Genentech: Consultancy, Research Funding. Christensen:Odense University Hospital: Current Employment; Seattle Genetics, Inc.: Research Funding. Morschhauser:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Domingo-Domenech:Takeda: Consultancy, Other: Travel, accomodations and expenses , Research Funding; Bristol-Myers Squibb: Other: Travel, Research Funding; Roche: Other: Travel, accomodations and expenses ; Janssen: Other: Travel, accomodations and expenses ; Seattle Genetics, Inc.: Research Funding. Rossi:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Kim:Donga: Research Funding; Joihnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Takeda: Research Funding; Celltrion: Research Funding. Feldman:Celgene: Honoraria, Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Rhizen: Research Funding; Janssen: Speakers Bureau; Pharmacyclics: Honoraria, Other, Speakers Bureau; AstraZeneca: Consultancy; Bayer: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Pfizer: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Trillium: Research Funding; Portola: Research Funding; Corvus: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding. Menne:Daiichi Sankyo: Honoraria; Kyowa Kirin: Other: Travel expenses; Pfizer: Honoraria, Other; Roche: Honoraria; Bayer: Other: Travel expenses; Kite/Gilead: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel expenses; Takeda: Honoraria; Atara: Honoraria; AstraZeneca: Research Funding; Amgen: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding. Belada:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding. Illés:Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharma: Consultancy, Honoraria; Solasia: Honoraria; SymBio: Consultancy; Takeda: Consultancy, Honoraria; HUYA Bioscience: Consultancy, Honoraria; Eisai: Honoraria; Yakult: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Chugai Pharma: Consultancy, Honoraria. Tsukasaki:Ono Pharma: Consultancy; Mundy Pharma: Honoraria; HUYA: Consultancy, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Eizai: Research Funding; Seattle Genetics: Research Funding. Yeh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Shustov:Seattle Genetics: Research Funding. Hüttmann:Lead Discovery Center GmbH: Consultancy; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment. Savage:Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria. Zinzani:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Miao:Takeda: Current equity holder in publicly-traded company. Bunn:Seattle Genetics: Research Funding; Takeda: Current Employment. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Puhlmann:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Truemper:Janssen: Consultancy; Mundipharma: Research Funding; Nordic Nanovector: Consultancy; Roche: Research Funding; Seattle Genetics: Research Funding; Takeda Europe: Consultancy, Research Funding.

BACKGROUND: CNS directed chemotherapy (chemo) reduces the risk of CNS relapse of ALL, but the optimal way to measure baseline CNS involvement is controversial. Baseline CSF testing can provide risk stratification and often dictates CNS prophylaxis (ppx) during initial treatment. Despite advances, up to 10% of adults still suffer CNS relapse (Blood 2008;112:1646, Cancer 2014;120:3660). Testing typically focuses on conventional cytospin (CC) of CSF, but CC is limited by interobserver variability and insensitivity (Blood 2014;124:3799). Alternatively, MFC is more sensitive (ASH 2018, #658). A previous study in children with ALL found leukemia detection in the CNS by CC or MFC at diagnosis to be associated with an increased risk of both isolated bone marrow and any CNS relapse (ASH 2018, #657). To our knowledge, this use of MFC has not specifically been studied in hyperCVAD, a commonly used chemotherapy regimen for the initial treatment of adult ALL. We hypothesized that baseline lymphoblast detection in the CSF by MFC is predictive of CNS relapse. METHODS: We included data collected from 11/6/07 to 6/22/20. Patients (pts) ≥18 years old who received ≥4 cycles (equivalent of cycle 2B) of hyperCVAD as first-line therapy were eligible. Pts must have had MFC done on CSF at baseline. Pts with mixed phenotype or insufficient follow-up data were excluded. CNS ppx with hyperCVAD historically uses intra-CSF (ie, intrathecal or intraventricular) methotrexate 12 mg on day 2 and cytarabine 100 mg on day 8 of each cycle for 6-12 doses without cranial radiation, though all patients were treated per physician discretion. CC and MFC results were taken from clinical reports and verified by an independent hematopathologist (Dr. Cherian). Baseline CSF positivity (CSF+) and negativity (CSF-) were defined by MFC, with any percentage of lymphoblasts considered CSF+. COG definitions of CNS status by CC were also used (J Clin Oncol 2016;34:2380). Univariate Cox models evaluated associations to CNS relapse. Kaplan-Meier curves were used to estimate the probabilities of overall survival (OS) and cumulative incidence of CNS relapse. RESULTS: We identified 92 eligible pts. Disease and treatment characteristics are summarized in Table 1, and results of initial CSF testing are shown in Table 2. Twenty-one pts were CSF+ by MFC at baseline: by CC, 6 of these were positive, 6 were negative, 7 were equivocal (ie, morphologic review was unable to rule out blasts), and 2 did not have baseline CC. None were positive by CC but negative by MFC. Eight of 29 (38%) with circulating blasts had a traumatic (>10 RBC/uL of CSF) first lumbar puncture (LP). Of these 8, 4 (50%) were CSF+. Five (5%) pts had an Ommaya reservoir placed during treatment. Pts received a median of 8 doses of intra-CSF chemo (range, 5-52). All but 7 pts (8%) received a combination of methotrexate and cytarabine like above. Twenty CSF+ pts (95%) achieved CSF- after a median of 1 dose of intra-CSF chemo (range, 1-5). Out of the 71 CSF- pts, none became CSF+ during initial treatment despite being tested a median of 5 times (range, 2-10). Eight pts (9%) had CNS relapse (3 isolated, 5 concurrent medullary relapse). Comparisons between baseline CSF testing, intra-CSF treatment, and CNS relapse are shown in Table 2. CSF+ pts received significantly greater doses of intra-CSF chemo. Of the 21 CSF+ pts, 5 (24%) had CNS relapse (2 isolated, 3 concurrent), and out of the 71 CSF- pts, 3 (4%) had CNS relapse (1 isolated, 2 concurrent; p=0.014). Among univariate models of CSF+ vs -, traumatic LP vs not, B vs T lineage, LDH, and WBC, only CSF+ was significantly associated with CNS relapse (hazard ratio 4.8, 95% confidence interval [CI] 1.2-20, p=0.031). Estimated 3-year cumulative incidence of CNS relapse for CSF+ was 15% vs 3.3% for CSF- (Figure 1). Median OS for the whole cohort was not reached, with estimated 3-year OS of 74% (95% CI, 65%-84%). CONCLUSIONS: MFC of CSF is more predictive of CNS relapse risk than CC in the context of front-line hyperCVAD, questioning the use of CC if MFC is performed. Further, CNS relapses were significantly more frequent when CSF+ despite administration of significantly more intra-CSF chemo. Traumatic LP per se did not increase risk of CNS relapse if CSF- by MFC. Surveillance during treatment by MFC in CSF- pts identified no cases of occult CNS relapse, arguing against this routine practice. Future studies should consider incorporating MFC of CSF into risk-adapted CNS-directed treatment strategies. Disclosures Shustov: Seattle Genetics: Research Funding. Becker:Accordant Health Services/Caremark: Membership on an entity's Board of Directors or advisory committees; Cardiff Oncology: Research Funding; SecuraBio: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; JW Pharmaceutical: Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Invivoscribe: Research Funding. Oehler:Takeda: Consultancy; BMS: Consultancy; Pfizer, Inc: Research Funding. Halpern:Bayer: Other; Novartis: Other; Jazz Pharmaceuticals: Other; Imago BioSciences: Other; Tolero Pharmaceuticals: Research Funding. Walter:Amgen: Consultancy, Research Funding; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding; StemLine: Research Funding; Selvita: Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding. Cassaday:Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding.

Background: Classical Hodgkin lymphoma (CHL) patients (pts) requiring second line therapy may still be cured with multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). The likelihood of long-term remission following ASCT for relapsed/refractory (R/R) CHL is predicted by response to pre-ASCT salvage therapy (Moskowitz et al. Blood 2012). The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) is effective as a single agent in R/R CHL. We hypothesized that concurrent therapy with dose-dense BV and 2 cycles of ICE would be safe, efficient, and produce high CR rates necessary for superior outcomes after ASCT. (#NCT02227199) Methods: Patients (pts) ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible for this IRB-approved prospective clinical trial. Treatment included BV on Days 1 and 8 at either 1.2 or 1.5 mg/kg (based on 3+3 dose-escalation schema; capped at 150 mg), ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2 daily on Days 1-3. Two 21-day cycles were given with G-CSF support. BV 1.5 mg/kg was selected as the phase II dose based on reported dose escalation data (ASH 2016, #1834). PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue (FFPET) from presentation and relapse were collected for correlative studies. Pre-treatment PB cytokine levels were measured by Luminex. Immunohistochemistry (IHC) on FFPET identified components of inflammatory microenvironment. The primary endpoint was to determine the MTD and CR rate after 2 cycles. Secondary endpoints included PFS, OS, stem cell collection, and molecular correlates. Results: All 45 pts have enrolled and completed study treatment, including 42 pts who were assigned treatment at the MTD of 1.5 mg/kg on day 1 and 8 of each cycle. Median age was 31 (range, 21-61). 16/45 (36%) were male, 28/45 (62%) had primary refractory disease, and 11/45 (24%) had extranodal involvement at relapse. 41 pts completed both cycles of therapy. One pt experienced grade 5 multi-system organ-failure during cycle 1, one pt was removed from protocol due to non-compliance, and two pts omitted cycle 2 due to toxicity (grade 4 sepsis, grade 3 Sweet syndrome attributable to G-CSF). 2 pts received all ICE dosing, but omitted at least one dose of BV due to toxicity. In addition, 13/41 (32%) pts delayed initiation of cycle 2 by a median of 7 days (range 6-17) due to toxicity, primarily elevated transaminases (10/13, 77%). 16/45 (36%) pts experienced neuropathy, but grade ≥2 neuropathy was rare (3/45, 7%). Other grade 3-4 non-hematologic toxicity included febrile neutropenia/sepsis (11%), elevated ALT (11%), hyperglycemia (7%), pulmonary embolism (4%), and elevated AST (4%). 36 pts underwent PBSC collection at our institution and had all data available for analysis. 30/36 pts were able to collect at least 5x106 CD34+ cells/kg. 5/6 of the remaining pts were still able to proceed with ASCT with the amount collected, and the other pt was not deemed an ASCT candidate due to social reasons. 37/43 pts (86%) who were evaluable for response proceeded to ASCT (2 subjects declined ASCT, 2 were ineligible due to social issues, one was lost to follow up, one remained chemorefractory despite additional salvage chemotherapy). Only 4/37 pts who received an ASCT subsequently relapsed. 43 pts were evaluable for efficacy. Overall response rate (ORR) and CR for all enrolled patients were 91% and 74%, respectively. Among primary refractory pts, ORR and CR were 86% and 68%, respectively. With a median follow-up of 26.5 months (range 0.7-62) months, 2-year PFS and OS were 82% and 98%. Updated results will be presented at the meeting. Conclusions: BV-ICE is a rapid, active and tolerable salvage regimen for R/R CHL patients, including those with primary refractory disease. Efficacy results are comparable to previously presented BV-chemo salvage combinations often delivered over longer durations. BV-ICE should be considered in R/R CHL prior to ASCT. Figure Disclosures Lynch: Juno Therpeutics: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Rhizen Pharmaceuticals: Research Funding; Bayer: Research Funding; Cyteir: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding. Cassaday:Merck: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Honoraria, Research Funding; Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Kite/Gilead: Consultancy, Research Funding. Smith:AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Karyopharm: Consultancy. Fromm:Merck: Research Funding. Cowan:Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Shustov:Seattle Genetics: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Gopal:IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy.

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.

The primary cutaneous CD30+ lymphoproliferative disorders are a family of extranodal lymphoid neoplasms that arise from mature postthymic T cells and localize to the skin. Current classification systems recognize lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma, and borderline cases. In the majority of patients, the prognosis of primary cutaneous CD30+ lymphoproliferative disorders is excellent; however, relapses are common, and complete cures are rare. Skin-directed and systemic therapies are used as monotherapy or in combination to achieve the best disease control and minimize overall toxicity. We discuss 3 distinct presentations of primary cutaneous CD30+ lymphoproliferative disorder and present recommendations for a multidisciplinary team approach to diagnosis, evaluation, and management of these conditions in keeping with existing consensus guidelines.

Background Patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy are at increased risk of developing therapy-related (t-) myelodysplastic syndrome (MDS). It is unclear whether antecedent CLL adds prognostic value to the revised International Prognostic Scoring System (IPSS-R) for MDS. We performed a retrospective analysis to evaluate the significance of a previous CLL diagnosis as an independent adverse prognostic factor. Patients and Methods We identified 18 consecutive patients with t-MDS, previously treated for CLL (CLL-MDS) from 2002 to 2016. For each CLL-MDS patient, we identified 2 control patients with de novo MDS matched for age (≤ 65 or > 65 years), IPSS-R (≤ 3 or > 3), and year of MDS diagnosis (before or after 2008). Multivariable models were developed to test for independent predictors of progression to acute myeloid leukemia (AML) and overall survival (OS). Results Median time from CLL to MDS diagnosis was 58.8 months (range, 12-280 months) and median number of treatment lines for CLL was 1 (range, 1-5), including alkylating agents in 15 patients (83%) and fludarabine, cyclophosphamide, rituximab in 12 patients (67%). Hypomethylating agents were administered in 13 (72%) of CLL-MDS patients and 33 (91%) of de novo MDS patients. After a median follow-up of 19.2 months, OS was not different between CLL-MDS and matched de novo MDS patients. CLL-MDS patients with IPSS-R score ≤ 3 had better OS compared with those with IPSS-R score > 3. In multivariate analysis, there was no significant independent association between history of CLL OS or progression to AML. Conclusion History of CLL did not independently affect OS in t-MDS patients beyond IPSS-R score.

Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T-cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty-seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression-free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem-cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy.

PEREIRA, JULIANA/0000-0002-0655-2821; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Trotman, Judith/0000-0001-8009-4593 WOS: 000462407900001 PubMed: 30707661 PURPOSEThe aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).PATIENTS AND METHODSAdult patients with relapsed/refractory PTCLone or more prior therapywere randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m(2) (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m(2) or intravenous romidepsin 14 mg/m(2) (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned.RESULTSBetween May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm.CONCLUSIONIn patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm. Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Funded by Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Summary Background Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sezary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sezary syndrome. Methods This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1–5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6–9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov , NCT02890368 , and was closed by the sponsor to focus on intravenous studies with TTI-621. Findings Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sezary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sezary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17–66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. Interpretation Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sezary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. Funding Trillium Therapeutics.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.

Introduction We examined patient characteristics, treatments and outcomes of transformed mycosis fungoides (tMF) patients from COMPLETE: a large, multicenter, prospective cohort study of peripheral T-cell lymphoma patients in the US. Methods Patients with tMF were enrolled in COMPLETE at the time of transformation. For this analysis, we identified tMF patients with completed baseline, treatment and follow-up records. Median survival was assessed using Kaplan-Meier methodology. Results Of the 499 patients enrolled in COMPLETE, 17 had tMF. Median age was 61; 53% were male, 9 had elevated lactate dehydrogenase (LDH) and 9 had lymph node involvement. About one-quarter of the patients were African American and 47% had CD30+ disease. Median time to transformation was 53 months. All patients received systemic therapy, with 19% receiving concomitant radiotherapy. Most patients (87%) received single agents, including liposomal doxorubicin, pralatrexate and gemcitabine. Eight patients (50%) had reported responses to therapy. Median survival was 18 months. One- and two-year survival rates were 56% and 44%, respectively. Conclusions tMF often express CD30 and present with lymph-node involvement. Responses have been seen with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes.

Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. Methods: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. Results: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. Conclusions: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

Summary Background Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL. Methods We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov , NCT01142674 . Findings 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20–61), overall survival at 5 years was 54% (95% CI 44–63) in patients with nasal disease (n=98) and 34% (27–46) in patients with extranasal disease (n=68). Interpretation To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL. Funding The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.

This phase 1 study evaluated frontline brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab vedotin monotherapy) in 26 patients with CD30+ peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.

Summary Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL‐NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL‐NOS were retained for study. At a median follow‐up of 46 months, the median overall survival (OS) and progression‐free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1–2), and high risk (HiR, 74 patients, 24%, score 3–4), having a 3‐year OS of 76% [95% confidence interval 61–88], 43% [35–51], and 11% [4–21], respectively (P

Leukemic phase of anaplastic large cell lymphoma (ALCL) is extremely rare. We present a case of primary cutaneous-ALCL (C-ALCL), who developed nodal involvement 4 years later. The patient was treated with combination chemotherapy and autologous stem cell transplantation; however, she relapsed 5 months later. At that time, the patient was given brentuximab vedotin (BV) with initial response. One year later, the patient demonstrated progressive adenopathy and leukemic involvement by her ALCL (comparative T cell clonality showed PCR products of the same size in the diagnostic skin and relapsed leukemic blood). Interestingly, the circulating tumor cells showed only subset expression of CD30 by flow cytometry (performed on peripheral blood). This patient demonstrates an unusual manifestation of ALCL (leukemic phase), with the additional confounder of CD30 downregulation, perhaps secondary to the BV therapy, or possible CD30-negative tumor escape.

HyperCVAD is a commonly-used regimen for adults with newly-diagnosed acute lymphoblastic leukemia (ALL). However, relatively little is known about the application of minimal residual disease (MRD) detection with this treatment. To address this, we studied 142 adults with ALL treated with hyperCVAD over a 10-year period who had MRD assessed by either multi-parameter flow cytometry or (for patients with Philadelphia chromosome positive ALL) reverse transcriptase polymerase chain reaction for the BCR-ABL1 translocation. In a multivariate analysis, patients who achieved MRD negativity (MRDNeg ) at any point had significantly better overall survival (OS; hazard ratio [HR] 0.43; P = .01) and event-free survival (EFS; HR 0.27; P < .01). Of 121 patients with MRD assessed at various points within 90 days of starting hyperCVAD, 50% (n = 61) had achieved MRDNeg . Among those that became MRDNeg , the median time to MRDNeg was 68 days. Time to MRDNeg was significantly associated with EFS (P = .009), but not OS (P = .19), implying increasingly better EFS the earlier MRDNeg is achieved. These data add to our understanding of MRD assessment during treatment with hyperCVAD, aide clinicians with predicting relapse risk, and provide additional historical data on which future clinical trials can be designed.

Introduction Infusional da-EPOCH-R (dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab) is a dose-intensified regimen with a potential role in treating high-risk subtypes of aggressive B-cell non-Hodgkin lymphoma (B-NHL). Studies of da-EPOCH-R use daily injections of granulocyte colony-stimulating factor (GCSF) to tailor chemotherapy dosing, and whether 1-time administration of pegylated GCSF (peg-GCSF) is as efficacious has not been addressed. Patients and Methods We reviewed aggressive B-NHL patients treated at our center with first-line da-EPOCH-R for clinician choice of growth factor, and analyzed dose level achieved, rate of unplanned hospitalizations, and patient outcomes. Results Among 73 patients, 44 received peg-GCSF. Overall, 11 patients (15%) patients achieved dose level 4. Baseline characteristics between peg-GCSF and GCSF groups were similar. The proportion of patients who achieved dose level 4 was comparable in the peg-GCSF group (5 of 44 [11%]) and daily GCSF (6 of 29 [21%]; P = .24). The rate of unplanned hospitalizations, and event-free and overall survival, were also similar between groups. Conclusion We suggest routine use of peg-GCSF is an acceptable alternative to daily GCSF, for patients in whom da-EPOCH-R is selected as first-line treatment for aggressive B-NHL.

Introduction The phase 3 ECHELON-2 study (NCT01777152) compared frontline treatment with brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30+ peripheral T-cell lymphomas (PTCL). At 5 years, A+CHP continues to provide clinically meaningful improvement in progression-free survival (PFS) (hazard ratio [HR] 0.70 [95% confidence interval {CI}: 0.53, 0.91], P=0.0077) and overall survival (OS) (HR 0.72 [95% CI: 0.53, 0.99], P=0.0424) vs CHOP. Ongoing remission was observed in ~60% of pts with sALCL, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy (Horwitz S, et al. ASH 2020). Due to the rarity of this disease and lack of data on prospective, uniformly treated pts, ECHELON-2 provides a large and unique prospective data set with potential utility in informing future studies of PTCL. Herein, we report a series of exploratory analyses in prespecified subgroups based on age, gender, and histology to supplement the data from the full 5-year analysis. Methods ECHELON-2 (N=452) is a randomized, double-blind, double-dummy, placebo-controlled, multicenter study. Eligible pts with previously untreated CD30+ PTCL were randomized 1:1 to A+CHP or CHOP for 6 or 8 cycles. Randomization was stratified by histological subtype and international prognostic index (IPI) score. The primary endpoint of PFS was assessed per blinded independent central review in the primary analysis and per investigator in this exploratory subgroup analysis. Outcomes by age Results Among all pts The potential association of gender with PFS outcomes varied within each treatment arm: males on the CHOP arm had higher PFS than females while females had higher PFS than males on the A+CHP arm (Table 2). In addition, the OS benefit of A+CHP vs CHOP was consistent for both genders (female, HR 0.68 [95% CI: 0.40, 1.16], P=0.1597; male, HR 0.73 [95% CI: 0.49, 1.08], P=0.1148). Females and males had similar OS within each arm (A+CHP, female vs male: HR 1.00 [95% CI: 0.61, 1.64], P=0.9966; CHOP, female vs male: HR 1.03 [95% CI: 0.66, 1.60], P=0. 9054). Among all pts with PTCL-NOS, the median PFS and OS were 13.57 months and 46.4 months. When assessing by treatment arm, the PFS (Table 1) and OS (HR 0.75 [95% CI: 0.37, 1.48], P=0.4003) HRs were similar to the intent-to-treat (ITT) population. Among all pts with AITL, the median PFS was 23.75 months and the median OS was not reached. When assessing by treatment arm, the PFS (Table 1) favored CHOP and OS was similar (HR 1.01 [95% CI: 0.40, 2.55], P=0.9855). In the sALCL subgroup, PFS was superior in those treated with A+CHP overall and across IPI subgroups: 0-1, 2-3, 4-5 (Table 1). OS was also longer in the A+CHP arm (HR 0.66 [95% CI: 0.43, 1.01], P=0.0529) overall and across IPI subgroups: 0-1 (HR 0.73 [95% CI: 0.20, 2.73], P=0.6411), 2-3 (HR 0.57 [95% CI: 0.32, 1.01], P=0.0496), and 4-5 (HR 0.89 [95% CI: 0.42, 1.89], P=0.7606). Conclusions ECHELON-2 results at 5 years demonstrate a generally consistent benefit of A+CHP over CHOP across subgroups and for the ITT population. Furthermore, this large prospective dataset of pts with PTCL has redefined efficacy outcomes for this population and provides important benchmark data to inform future studies. Figure 1 Figure 1. Disclosures Horwitz: Affimed: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Aileron: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Savage: Astra-Zeneca: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Illidge: Seagen Inc.: Research Funding. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Shustov: Seagen Inc.: Research Funding. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Koch: Seagen Inc.: Research Funding. Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Fenton: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Campana: Seagen Inc.: Research Funding. Dong: Seagen Inc.: Research Funding. Truemper: Seagen Inc.: Research Funding.

Introduction ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) represents standard frontline therapy for classical Hodgkin lymphoma (CHL) in North America. Substituting brentuximab vedotin for bleomycin in this regimen demonstrated improved efficacy in advanced stage patients (pts) but also increased toxicity (Connors et al NEJM 2017). PD-1 inhibitors are highly active in relapsed/refractory CHL, and the first-line setting may represent the ideal time for incorporating PD1 inhibition given the relatively intact host immunity and juxtaposition of malignant cells with T cells in the tumor microenvironment. Methods This was a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requiredECOG 0-1, adequate organ function, and measurable disease. The trial intended to enroll 30 pts. AVD was given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab (200 mg IV) was given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective was to estimate the safety of delivering 2 cycles of APVD. The secondary objective was to estimate the FDG-PET2 negative (Deauville score 1-3) rate after 2 cycles of APVD. Exploratory objectives included overall and progression free survival, predictive capacity of PET2 after APVD, analysis of ctDNA as well as assessments of metabolic tumor volume. After PET2 response assessment, subjects could continue APVD for up to 6 total cycles as deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy). Results All 30 subjects have enrolled and received at least 2 cycles of therapy. Median age was 32 years (range 18-69). Most pts had advanced stage (stage I n =1 (3%), stage II n=11 (37%), stage III n=7 (23%), stage IV n=11, (37%)). Thirteen (43%) pts had B symptoms at diagnosis and 5 (17%) had bulky disease. Among the 30 pts enrolled, 28 are evaluable for response (one pt declined interim-PET and further treatment and final patient will have PET2 shortly after abstract deadline.Nineteen (68%) pts were PET2 neg (5PS 1-3). No PET2+ pts have progressed to date. End of therapy (EOT) PET negativity (after 2-6 cycles) was 78% (18/23). Among the 5 pts with residual FDG uptake at EOT, only 1 (20%) has developed recurrent lymphoma. With median follow-up of 10.3 months, 1-year PFS and OS were 96% and 100%, respectively. Six (20%) pts required interruption of pembrolizumab due to toxicity, primarily grade ≥ 2 transaminitis (83%). Those with grade 2 transaminitis (2/6) completed chemotherapy prior to resolving to grade 1 and did not receive additional pembrolizumab. Those with grade ≥ 3 transaminitis (3/6) were required to permanently discontinue pembrolizumab. All transaminitis was transient and resolved with steroids and/or withholding pembrolizumab. No pneumonitis and no other grade ≥ 3 immune-related AEs were observed. Toxicities were otherwise similar to those expected with ABVD chemotherapy. No pt had a treatment delay of > 21 days during the first 2 cycles, and no pt who interrupted pembrolizumab due to toxicity has relapsed. Updated efficacy and more detailed safety data will be presented at the meeting. Conclusion Pembrolizumab + AVD without a PD-1 lead-in is safe and effective therapy for frontline HL. In this study, PET2+ following APVD does not appear to be associated with high risk of disease relapse. Additional analyses of MTV and ctDNA are ongoing to better understand these results. Concurrent APVD, without an anti-PD-1 run-in, represents a well-tolerated, and efficacious backbone that can be further evaluated in all stages of CHL. Figure 1 Figure 1. Disclosures Lynch: Incyte: Research Funding; TG Therapeutics: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; SeaGen: Research Funding; Bayer: Research Funding; Juno Therapetics: Research Funding; Morphosys: Consultancy. Ujjani: ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Smith: Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Ignyta (spouse): Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Ayala (spouse): Research Funding; De Novo Biopharma: Research Funding; KITE pharm: Consultancy; Genentech: Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb (spouse): Research Funding; Incyte: Consultancy; Bayer: Research Funding; Beigene: Consultancy, Research Funding; Millenium/Takeda: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Shustov: Seagen Inc.: Research Funding. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Alizadeh: Gilead: Consultancy; Janssen Oncology: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Bristol Myers Squibb: Research Funding; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Gopal: Epizyme: Consultancy, Honoraria; MorphoSys: Honoraria; Gilead: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Teva: Research Funding; Beigene: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Acrotech: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Astra-Zeneca: Research Funding; Agios: Research Funding; Bristol Meyers Squibb: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Kite: Consultancy, Honoraria.

BACKGROUND: Novel agents added to front-line treatments for adult ALL yield high rates of measurable residual disease (MRD) negativity and survival. However, these approaches are infeasible outside large centers and in lower-resource settings. HyperCVAD is commonly used regardless of Philadelphia chromosome (Ph) status but has limitations, particularly in older patients (pts). Because of its efficacy for high-grade lymphomas (NEJM 2013, p. 1915), we hypothesized that DA-EPOCH would be active and safe in adult ALL. METHODS: Details of this study have been reported (ASH 2018, #1519; NCT03023046). Adults with newly-diagnosed ALL were eligible if not candidates for pediatric-inspired therapy (ie, Ph+, age ≥ 40). DA-EPOCH was given with G-CSF (Blood 2002, p. 2685). After treatment of the 1 st 5 pts, the dose-adjustment paradigm was employed once cytopenias were not due to ALL, typically after cycle 2. If Ph+, imatinib (IM) 600 mg or dasatinib (DAS) 100 mg daily on Days 1-14 of each cycle was added. If CD20+, rituximab 375 mg/m 2 was given once per cycle regardless of Ph status. Up to 8 cycles could be given followed by maintenance (POMP ± TKI) or allogeneic transplant (HCT). Pts with WBC > 30K/µL or LDH > 3x upper limit of normal at diagnosis received 10 doses of intrathecal methotrexate as CNS prophylaxis, and others received 8. Response was determined by bone marrow aspirate morphology (morph), multiparameter flow cytometry (MFC) and (for Ph+) BCR-ABL RT-PCR, with complete molecular response (CMR) assigned when the latter was undetectable. When MRD- by MFC (MFC-) per EuroFlow criteria (Leukemia 2010, p. 521), high-throughput sequencing-based MRD testing (HTS; ClonoSEQ) was performed. IKZF1plus was identified by chromosomal microarray as defined previously (JCO 2018, p. 1240). The primary endpoint was rate of MFC- remission within 4 cycles of therapy. Based on an institutional historical rate of MFC- after ≤ 4 cycles of 50% with hyperCVAD + TKI for Ph+ ALL (Am J Hematol 2018, p. 546), we defined success if we observed such remissions in ≥ 70%. A Simon 2-stage design with α = 0.09 and 80% power led to a sample size of 28 pts and success if ≥ 18 were MFC- after ≤ 4 cycles. For Ph-, we enrolled in cohorts (up to 25 total pts) if the upper bound of a 90% confidence interval (CI) stayed ≥ 59%, our historical rate with hyperCVAD. Follow-up provided to 7/1/21. RESULTS: 53/54 enrolled pts were evaluable. Baseline characteristics are in Table 1 and response rates in Table 2. For Ph+ ALL, 20 of 28 pts (71%; 90% CI = 54-85%) reached MFC- after ≤ 4 cycles; TKI used was DAS for 23 pts and IM for 5 pts. In Ph- ALL, 16 of 25 pts (64%; 90% CI = 46-80%) were MFC- after ≤ 4 cycles. Median follow-up of survivors was 22 months (mo; range: 4-50 mo). Median and 2-yr EFS were 15 mo and 32% (respectively); median OS was not reached, and 2-yr OS was 70% (Figure). In those age > 60 yrs, 2-yr EFS was 49% and OS was 71%. In univariate Cox models, neither WBC, age, adverse-risk cytogenetics, IKZF1plus, nor MFC- after ≤ 4 cycles were significantly associated with EFS or OS; the strongest was high-risk WBC with EFS (hazard ratio 2.1, p = 0.068). In sum, 36 pts reached MFC-: relapse occurred in 12 of 23 pts (52%) given maintenance therapy vs 4 of 12 pts (33%) who received HCT (p = 0.48 by Fisher exact test). Of 18 pts without MRD by HTS, 9 (50%) relapsed. None of the 6 pts given blinatumomab for MRD after DA-EPOCH have relapsed. Four pts (8%) had isolated CNS relapse. 44 pts (83%) developed ≥ 1 Grade (Gr) 3+ non-hematologic (heme) AE related to DA-EPOCH, with a mean of 2 per pt. Those seen in ≥ 10% of pts were febrile neutropenia/infection (23 Gr 3, 2 Gr 4); mucositis (7 Gr 3); and ALT increase (6 Gr 3). There was only 1 treatment-related death (2%; gastric hemorrhage). Twelve pts (23%) discontinued due to acute or cumulative toxicity. As for heme AEs in pts treated after cycle 1 (ie, when ALL was not the cause), only 15 pts (34%) had a Gr 4 platelet count at any time. CONCLUSIONS: DA-EPOCH yields comparable response and survival rates (with manageable toxicity) as more logistically-complex therapies in primarily high-risk ALL. When TKI was added for Ph+ disease, rates of MFC- exceeded the predefined threshold for success. Its efficacy and safety profile make it an appealing backbone to which novel agents may be added. Pending results of ongoing multivariable analyses comparing DA-EPOCH to historical treatments, DA-EPOCH could be considered a standard option, particularly in older adults and/or lower-resource settings. Figure 1 Figure 1. Disclosures Cassaday: Pfizer: Consultancy, Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Merck: Research Funding; Vanda Pharmaceuticals: Research Funding. Percival: Abbvie: Research Funding; Nohla Therapeutics: Research Funding; Cardiff Oncology: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; BMS/Celgene: Research Funding; Pfizer: Research Funding; Oscotec: Research Funding; Trillium: Research Funding. Halpern: Gilead: Research Funding; Abbvie: Consultancy; Agios Pharmaceuticals: Research Funding; Tolero Pharmaceuticals: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Imago Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Agios: Consultancy; Nohla Therapeutics: Research Funding; Pfizer: Research Funding. Becker: Glycomimetics: Research Funding; CVS Caremark: Consultancy; Abbie: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Cardiff Oncology: Research Funding; SecuraBio: Research Funding. Oehler: BMS: Consultancy; OncLive: Honoraria; Takeda: Consultancy; Pfizer: Research Funding. Shustov: Seagen Inc.: Research Funding. Orozco: Actinium Pharmaceuticals, Inc.: Other: site PI for clinical trial(s) sponsored by Actinium, Research Funding. Walter: BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Rituximab is not FDA approved for the treatment of acute lymphoblastic leukemia.

Objective Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design This phase 3, double-blind study (NCT01777152) randomized patients aged ≥18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/retreatment therapies. Results 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index ≥2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profile, including continued resolution/improvement of PN. Funded by NIH/NCI Support Grant P30 CA008748.

Peripheral T-cell lymphoma and natural killer/T-cell lymphomas (PT/NKCL) make up a diverse subgroup of non-Hodgkin's lymphomas characterized by an aggressive clinical course. The use of hematopoietic stem cell transplantation (HSCT) in the treatment of PT/NKCL remains controversial because of the absence of randomized controlled trials. The best available data suggest that certain subtypes of PT/NKCL may benefit more from the application of HSCT than other subtypes and that this benefit results from their unique clinical characteristics and underlying biology. Ultimately, however, prospective randomized controlled trials are needed to clarify the optimal type and timing of HSCT in patients with PT/NKCL.

Background With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. Patients and Methods We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States. Results A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P = .01). Conclusion The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organization classification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). We previously reported that adding pembrolizumab to RCHOP (PR-CHOP), shows no significant additive toxicity and a promising 2-year progression free survival of 83% (Smith B J Haem 2019), with no progression events among 19 pts with known PDL-1+ tumors. In that analysis, we noted 83% of patients had tumor PDL-1 expression by IHC using a centralized standard assay, including 18/23 (78%) and 13/23 (56%) demonstrating positivity in ≥5% and ≥30% of lymphoma cells respectively. Herein we report long-term clinical follow up, as well as results of high-resolution molecular karyotyping using chromosome genomic array testing (CGAT), to assess whether 9p24.1 abnormalities explained the extent of PDL1 tumor expression. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3 B follicular lymphoma eligible for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. There was no maintenance or consolidation therapy. Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). CGAT was performed from DNA extracted from formalin-fixed, paraffin-embedded tissue sections using the OncoScan platform (ThermoFisher). H&E slides of adjacent sections of the tissue used for CGAT were evaluated by a pathologist to ensure a minimum of 30% tumor content. Patients were followed for relapse and survival. Results: Among 30 treated pts with a median follow up of 32 months, there have been no additional DLBCL relapses or deaths since the published report. There has been one relapse of follicular lymphoma in a patient with initial composite lymphoma , who is now in remission 1 year after autologous stem cell transplantation. 3-year estimated PFS is 83% and OS is 86%. On univariate analysis, only tumor bulk 7.5 cm or greater (p=.02) and absence tumor PDL-1 expression by IHC (p=.001) predicted inferior PFS. Tumor bulk, (p=.03), IPI 3 or higher (p=.01), and absence of tumor PDL-1 expression (p=.001) predicted worse overall survival. PFS and OS were unaffected by cell of origin by IHC, double expresser status, or diagnosis to treatment interval greater than median (29 days). Regarding safety, there were late cases of paraneoplastic pemphigus and rheumatoid arthritis 5 and 8 months from last dose of pembrolizumab, respectively. Both of these were managed successfully with immunosuppression. Chromosome genomic array testing CGAT) was performed to assess copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH), particularly for the presence of gains or amplifications involving locus 9p24.1, containing the CD274 (PDL1) gene. Of 15 tested pretreatment baseline diagnostic tissue specimens, 14 provided informative result with 12 abnormal and 2 normal. Notably, no gain or amplification in 9p24.1 were seen; there was one case of deletion and 1 with cnLOH. The percent genome altered among abnormal cases ranged from 2% to 37% (median 12%). Complex karyotype, defined as genomic aberrations involving at least 3 chromosome arms (or % genome altered greater than 5% by CGAT), was seen in 10/14 pts (71%). This 14-sample data set included 6/14 pts with >30% PDL1 tumor expression (and 10 with 5% or greater PDL1-tumor expression). Conclusions: No additional safety signals have been observed, and PFS/OS remain favorable for the combination of pembrolizumab + RCHOP in this single arm trial with the best results in PDL-1+ disease. Despite frequent tumor PDL1-expression at baseline, no gains or implications of 9p24.1 were observed suggesting alternative mechanisms for overexpression of PDL-1. Further study this regimen and others testing combinations of immune checkpoint inhibition with first-line DLBCL therapy are warranted, to better ascertain the potential superiority of this strategy in this setting. Disclosures Smith: Portola: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; De Novo Biopharma: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Bristol Meyers Squibb: Research Funding. Fromm:Merck: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Lynch:Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Juno Therpeutics: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding; Cyteir: Research Funding. Cowan:Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Abbvie: Research Funding. Ujjani:Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding. Cassaday:Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Merck: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding. Gopal:Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding.

Background: Ibrutinib (I) and venetoclax (V) have each demonstrated modest single-agent activity in relapsed/refractory follicular lymphoma (FL) (Gopal A, JCO 2018; Davids M, JCO 2017). Preclinical data have shown synergy with these agents in B-cell cell lines (Kuo H, Mol Cancer Ther 2017). Based on these observations, we proposed the first trial to combine I and V in FL. Results from the phase Ib portion of this multi-institutional investigator-initiated trial are presented here (NCT02956382). Methods: This phase Ib/II trial is open at Georgetown/Lombardi CCC, Hackensack/John Theurer CC, and University of Washington/Fred Hutchinson/Seattle Cancer Care Alliance. Eligibility criteria include WHO grade 1-3a FL, >1 prior systemic therapy, measurable disease warranting therapy by standard criteria or physician discretion, ECOG performance status < 2, adequate marrow, hepatic, renal function. Patients (pts) were enrolled in a standard phase I 3+3 design at a starting dose level (DL) of I 420 mg daily, V 400 mg daily (DL0). The highest initially planned dose level was DL3: I 560 mg daily, V 800 mg daily. There was no dose ramp up of V based on monotherapy experience in FL. Pts at high risk for tumor lysis syndrome (TLS), defined as node ≥ 8 cm and/or significant lymphocytosis, were hospitalized for initial dose. Pts received study drugs until progression or unacceptable toxicity. Response was assessed by PET-CT and bone marrow biopsy (if marrow involvement present at time of enrollment). Results: Sixteen pts were enrolled between November 2017 - May 2020. Median age was 66 years (range 50-87); 75% were male; 75% were Stage III/IV, 94% had WHO grade 1/2 FL (Table 1). FLIPI score at enrollment was 25% low risk, 44% intermediate risk, 31% high risk. Two pts were considered high risk for TLS. Pts received a median of 2 prior therapies (range 1-8); 19% were refractory to last line of therapy. Cohort enrollment was: DL0 (n=3), DL1 (n=6), DL2 (n=6), DL3 (n=1). The protocol was amended to close DL3 based on pharmacokinetic data from DL2 indicating a 1.8-fold higher mean steady-state ibrutinib plasma exposure compared to ibrutinib 560 mg monotherapy and concern for potential toxicity. Grade 3 adverse events (AE) included neutropenia (25%), thrombocytopenia (13%), lung infection (13%), upper respiratory infection (6%), neutropenic fever (6%), atrial fibrillation (6%), ALT/AST elevations (6%), mucositis (6%), failure to thrive in setting of progression (6%), abdominal pain (6%). There were no grade 4/5 AE. Grade 1/2 AE occurring in > 20% of pts included diarrhea (75%), nausea (63%), bruising (38%), rash (31%), headache (31%), constipation (25%), fatigue (25%). There was no evidence of clinical TLS; 19% had grade 1 hyperuricemia. The pt enrolled at DL3 had grade 1 diarrhea, grade 1 neutropenia. One dose limiting toxicity (DLT) occurred at DL1 (I 560 mg, V 400 mg): grade 3 neutropenia with fever and infection. There were no other DLTs. Therefore, DL2 (I 560 mg, V 600 mg) was determined to be the recommended phase 2 dose (RP2D). The ORR was 69% (0.413, 0.890); CR 25% (0.073, 0.524). The ORR at the RP2D was 83% (CR 33%). Responses by dose level are listed in Table 2. The regimen demonstrated activity in the bone marrow; 2 pts had eradication of involvement and 1 had a decrease from 60% to 0.5% by flow cytometry. Response by lines of prior therapy: 1 (86%, 6/7), > 2 (56%, 5/9). Most pts (91%) had a response by time of first assessment (12 weeks). The median progression-free survival (PFS) was 8.3 months (5.6 months, NA) (Figure 1). Of note, 2 responding pts chose to withdraw from study due to travel and were censored in the PFS analysis at time of discontinuation. One remained in a CR at least 9 months after study withdrawal as documented by PET-CT performed off protocol. No pts discontinued due to toxicity. Conclusion: In the first clinical trial to combine a BTK inhibitor and a BCL-2 inhibitor in relapsed/refractory FL, we found the I-V doublet to demonstrate a toxicity profile similar to that seen in mantle cell lymphoma and CLL. While our sample size is small, there was no evidence of clinical TLS, despite omission of the V ramp up. Preliminary results of anti-tumor activity are encouraging and further evaluation at the RP2D (I 560 mg, V 600 mg) is ongoing in the phase II trial. The combination of ibrutinib and venetoclax may provide an effective option for FL, utilizing a targeted approach distinct from other novel agents currently approved for this malignancy. Disclosures Ujjani: Verastem Oncology: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Atara: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Gilead/Kite: Consultancy, Research Funding. Lai:Agios: Consultancy; Macrogenics: Consultancy; Astellas: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy. Leslie:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Broome:sanofi: Honoraria; argenx: Honoraria; apellis: Honoraria; Alexion: Honoraria. Gopal:IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding. Smith:Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Portola: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy. Till:Mustang: Patents & Royalties, Research Funding. Lynch:Morphosys: Consultancy; Takeda: Research Funding; Bayer: Research Funding; TG therapeutics: Research Funding; Incyte: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; Rhizen: Research Funding. Shadman:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Gilead: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Ended employment in the past 24 months; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maloney:Novartis: Consultancy, Honoraria; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Cheson:TG Therapeutics: Speakers Bureau; Symbio: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Trillium: Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Parexel: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: We are presenting data regarding the use of venetoclax and ibrutinib in follicular lymphoma.

BACKGROUND Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. METHODS Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. RESULTS Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]). CONCLUSIONS To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174–1183. © 2016 American Cancer Society.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.

Background The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. Methods Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. Results Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). Conclusions This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkin lymphoma often accompanied by autoimmune and paraneoplastic phenomena. Up to 50% of patients with AITL present with skin manifestations. This case series highlights two cases of AITL presenting with unusual cutaneous findings: one with a medium-vessel vasculitis and another with a chronic urticarial eruption. Clinicians should consider AITL in the differential diagnosis of vasculitis or urticaria refractory to standard treatment.

Background: Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. We hypothesized that the first-line immunologically-replete setting may be an opportune time for introducing PD-1 inhibition. We thus evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Methods: Eligible patients were age 18 or older, had adequate organ function, and had DLBCL or grade 3B FL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP for 6 cycles, every 21 days, measuring toxicity as the primary endpoint. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Findings: Among 30 treated patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. Only 1 of 4 partial responders has progressed. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 tumor expression was associated with non-GCB subtype, and improved PFS and survival.InterpretationPembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, and supports further trials evaluating PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy. Trial Registration: NCT02541565. Funding Statement: In addition to primary funding from Merck Sharpe and Dohme Corp, the authors recognize additional support from grant K24CA184039, NIH/NCI Cancer Center Support Grant P30 CA015704, and donations from Frank and Betty Vandermeer and Sonya and Tom Campion. Declaration of Interests: S.D.S. reports grants and nonfinancial research support from Acerta Pharma BV, Astrazeneca, De Novo Biopharma, Genentech, Jannsen Pharmaceuticals, Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, and Seattle Genetics; S.D.S.’ spouse receives research support from Ayala, Bristol Myers Squibb, Merck Sharp Dohme Corp, and Ignyta. S.D.S reports personal fees from Merck Sharp and Dohme Corp and Astrazeneca. A.K.G. reports grants and nonfinancial research support from Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector; Personal fees and nonfinancial support from Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Compliment, Asana Bio, and Incyte. H.R., K.B., J.V., Q.W. report no relevant financial disclosures. M.S. reports grands and nonfinancial research support from Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck Sharp and Dohme Corp; personal fees and nonfinancial support from Abbvie, Genentech, Astra Zeneca, Sound Biologics, Verastem, ADC therapeutics and Atara Biotherapeutics. B.G.T. reports grants and nonfinancial research support from Mustang Bio and RocheGenentech, and patents/royalties from Mustang Bio. R.C.L. reports grants and nonfinancial research support from Incyte Corporation, TG Therapeutics, Takeda, Juno Therapeutics, Rhizen Pharmaceuticals. A.J.C. reports grants and nonfinancial research support from Janssen, AbbVie, Juno Therapeutics, and Celgene; personal fees and nonfinancial support from Celgene. C.U. reports grants and nonfinancial research support from Pharmacyclics, Abbvie, and Celgene; personal fees and nonfinancial support from Amgen, bayer, Pfizer, Gilead, Astrazeneca, Genentech, Pharmacyclics, Abbvie, and Atara. A.R.S. reports grants and nonfinancial research support from Seattle Genetics, Spectrum Pharmaceuticals, and personal fees and nonfinancial support from Kyowa Hakko Kirin. R.D.C reports grants and nonfinancial research support from Merck Sharp and Dohme Corp., Incyte, Seattle Genetics, Vanda Pharmaceuticals, Amgen, Pfizer, Kite/Gilead; and personal fees and nonfinancial support from Amgen, Pfizer, Jazz, and Adaptive Biotechnologies. Ethics Approval Statement: This study was approved by the Fred Hutchinson Cancer Center- University of Washington Consortium IRB and all patients provided written informed consent to participate in the trial.